Isoxazol amides of 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylic acid-7,7-dioxide

ABSTRACT

This invention relates to novel amides of 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylic acid-7,7-dioxide having the Formula I: ##STR1## wherein R 1  is hydrogen, halogen or lower alkyl; R 2  is hydrogen, lower alkyl or aryl; Ar is aryl or heterocyclic; to the pharmaceutically acceptable salts thereof; and to processes for their preparation. The compounds of this invention exhibit antiinflammatory activity.

This is a division, of application Ser. No. 749,491 filed Dec. 10, 1976now U.S. Pat. No. 4,082,757.

DESCRIPTION OF THE INVENTION

This invention relates to novel amides of4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylic acid-7,7-dioxide havingthe Formula I: ##STR2## wherein R₁ is hydrogen, halogen or lower alkyl;R₂ is hydrogen, lower alkyl or aryl; Ar is aryl or heterocyclic andpharmaceutically acceptable salts thereof.

This invention also includes within its scope novel processes forpreparing the above compounds as well as the intermediates employed intheir synthesis.

Compounds of the Formula I are obtained by reacting a substituted5,6-dihydro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxylate of the FormulaII: ##STR3## wherein R₁ and R₂ are as defined above in Formula I and R'is lower alkyl, in acetic acid with hydrogen peroxide to obtain acorrespondingly substituted4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide of theFormula III: ##STR4## wherein R₁, R₂ and R' are as defined above inFormula II, which is heated with an appropriate amine in a suitable highboiling solvent, typically xylene, to obtain Compound I. Amines havingthe formula:

    NH.sub.2 --Ar

are suitable for use in this reaction, wherein Ar is a monocyclicaromatic hydrocarbon; a substituted monocyclic aromatic hydrocarbonwherein the substituent may be halogen, lower alkoxy, trifluoromethyland the like; a monocyclic heterocycle; or a substituted monocyclicheterocycle wherein the substituent may be halogen, lower alkoxy,trifluoromethyl and the like. Typical amines include aniline,amino-substituted pyridine, amino-substituted isoxazole,amino-substituted thiazole and the like.

The starting material II is prepared as described in copending U.S.application Ser. No. 749,507 filed Dec. 10, 1976 now U.S. Pat. No.4,092,325 Jagadish C. Sircar, Stephen J. Kesten and Harold Zinnes,"5,6-Dihydro-4-Oxo-4H- Thieno[2,3-b]Thiopyran-5-Carboxamides" byrefluxing a correspondingly substituted5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one with a sodium alkoxide and a(dialkyl)oxalate in an appropriate solvent. According to this procedure,a 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one (prepared as described inBull. Soc. Chim. Fr. 2172 (1966) or chemically known, obvious variationsthereof) is reacted with a sodium alkoxide, such as sodium methoxide anda (dialkyl)oxalate such as dimethyloxalate, in an appropriate solventsuch as benzene to obtain an alkyl4-hydroxy-α-oxo-6H-thieno[2,3-b]thiopyran-5-acetate, which is subjectedto decarbonylation in the presence of powdered glass, at about 170°C.-180° C. to obtain the desired alkyl5,6-dihydro-4-oxo-4H-thieno-[2,3-b]thiopyran-5-carboxylate, II.

The compounds of this invention having Formula I exhibitantiinflammatory activity. When tested in a modification of theprocedure described by Winter, et al., "Carrageenan Induced Edema inHind Paw of the Rat for Anti-inflammatory Drugs", Proc. Exptl. Biol. andMed. 111:544-547(1962). Thus, for example, when administered orally orintraperitoneally to rats at a dose of 6.25 to 100 mg/kg, they are ableto cause reduction in swelling of the paw induced by an irritant such ascarrageenin.4-hydroxy-N-(2-pyridyl)-6H-thieno[2,3-b]-thiopyran-5-carboxamide7,7-dioxide, when administered at a dose of 6.25mg/kg, demonstratesantiinflammatory activity in the rat in this test.

The compounds of this invention having Formula I are administered asaqueous suspensions or as aqueous solutions of their alkali metal salts.

The following definitions apply to all of the compounds, intermediatesand processes of this invention: lower alkyl is meant to include 1 to 7carbon, preferably 1 to 4 carbon, straight or branched alkyl chains;aforementioned definition of lower alkyl applies to the alkyl portion ofthe term lower alkoxy; halogen is meant to include chlorine, bromine andiodine; aryl is meant to include monocyclic aromatic hydrocarbons;substituted moncyclic aromatic hydrocarbons wherein the substituent maybe halogen, lower alkoxy, trifluoromethyl and the like; monocyclicheterocycles; and substituted monocyclic heterocycles wherein thesubstituent may be halogen, lower alkoxy, trifluoromethyl and the like.

In order to further illustrate this invention, the following examplesare provided:

EXAMPLE 1 ##STR5## Methyl4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate 7,7-dioxide

To a cooled (17°) suspension of methyl5,6-dihydro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxylate (34.8 g,0.1326 mole) in acetic acid (348 ml) is added dropwise 30% hydrogenperoxide (172.4 g, 1.526 mole). The mixture is stirred at roomtemperature for 2 hrs. when a clear solution is formed. The solution isstirred at room temperature for an additional 4 hrs. It is then heatedon a steambath for 12 min. to 94° C. and cooled immediately in anice-bath. At around 18° C. the product started to crystallize out. It isdiluted with water (696 ml) and the mixture stirred at room temperaturefor 16 hrs. The solid ester is collected and recrystallized frommethylene chloride-methanol mixture to give 12.3 g (31%) of whitecrystalline solid, m.p. 159°-162° C. An analytical pure sample, m.p.159°-162° C. is obtained as white crystalline solid by furtherrecrystallization from ethanol-methylene chloride. Yield 11.8 g (30%).

IR (CHCl₃) 3140 (OH); 1660 (C═O); 1620 (C═C--C═O); 1160 (SO₂) cm⁻¹.

NMR (CDCl₃) δ 12.7 (s, 1, OH, exchangeable); 7.5 (two d, 2, C₂,C₃); 4.3(s, 2, C₆ -H₂); 3.85 (s, 3, OCH₃). λ_(max) ^(EtOH) 320 (7,000), 240(17,600) cm⁻¹.

Anal. Calcd. for C₉ H₈ O₅ S₂ : C, 41.53; H, 3.10; S, 24.64. Found: C,41.58; H, 3.11; S, 24.59, 24.68.

EXAMPLE 2 ##STR6##4-Hydroxy-N-(2-pyridyl)-6H-thieno[2,3-b]thiopyran-5-carboxamide7,7-dioxide

A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate7,7-dioxide (7.2 g; 0.028 mole), 2-aminopyridine (3.9 g; 0.042 mole) andxylene (720 ml) is refluxed for 2 hrs. in a Soxhlet apparatus, thethimble of which contains 20 g of Linde type 4A molecular sieve when ayellow solid crystallized out. The mixture is cooled to 5° in anice-bath and the resulting crystalline precipitate is collected. It isrecrystallized from THF to give 2.55 g of material, m.p. 194°-195° C.The xylene-filtrate is refluxed as before for an additional period of 3hrs. It is concentrated to 300 ml, cooled and filtered to give a secondcrop, which is recrystallize for THF to give 1.5 g of the product, m.p.193°-194° C. An analytical pure sample, m.p. 194°-195° C. is obtained asyellow crystalline solid by further recrystallization from DMF-ethanolmixture.

IR (Nujol) 3160-3060 (broad, NH and OH) 1650 (C═O); 1620 (NH); 1150(SO₂) cm⁻¹.

NMR (DMSO) δ 10.8 (b, 1, NH); 8.5-7.1 (m, 6, aromatic), 4.6 (s, 2, CH₂).λ_(max) ^(EtOH) 368 (12,800), 265 (16,800), 242 (16,400) mμ.

Anal. Calcd. for C₁₃ H₁₀ N₂ O₄ S₂ : C, 48.44; H, 3.13; N, 8.69; S,19.89. Found: C, 48.47; H, 3.30; N, 8.98; S, 19.77, 19.65.

EXAMPLE 3 ##STR7##4-Hydroxy-N-(5-methyl-3-isoxazolyl)-6H-thieno[2,3-b]thiopyran-5-carboxamide7,7-dioxide

A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate7,7-dioxide (3.1 g, 0.012 mole), 3-amino-5-methylisoxazole (1.5 g, 0.015mole) and xylene (120 ml) is refluxed for 1.5 hrs. in a Soxhletapparatus, the thimble of which contains 15 g of Linde type 4A molecularsieve. The mixture is cooled to 5° C. in an ice-bath, and the resultingcrystalline precipitate is collected. The filtrate is refluxed for twoadditional hours and then cooled to give a second crop. The twofractions are combined and recrystallized from CH₂ Cl₂ --CHCl₃ mixtureto give a off-white crystalline solid (2.2 g, 56%), m.p. 209°-210° C.

IR (Nujol) 3290-3100 (b, NH, OH); 1630 (C═O); 1570 (NH); 1150 (SO₂)cm⁻¹.

NMR (DMSO) δ 11.2 (b, ˜2, NH, OH, exchangeable); 8.1 (d, 1, C₂); 7.5 (d,1,C₃); 8.63 (s, 1, C₄ '), 4.5 (m, ˜3, C₅,C₅); 2.4 (s, 3, C₆ ',CH₃).λ_(max) ^(EtOH) 350 (6,200); 254 (17,200) mμ.

Anal. Calcd. for C₁₂ H₁₀ N₂ O₅ S₂ : C, 44.17; H, 3.09; N, 8.58; S,19.65. Found: C, 44.01; H, 3.09; N, 8.58; S, 19.45, 19.42.

EXAMPLE 4 ##STR8##4-Hydroxy-N-phenyl-6H-thieno[2,3-b]thiopyran-5-carboxamide 7,7-dioxide

A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate7,7-dioxide (6.3 g, 0.024 mole), aniline (3 ml, 0.033 mole) and xylene(200 ml) is refluxed for 3 hrs. in a Soxhlet apparatus, the thimble ofwhich contain 20 g of Linde 4A molecular sieve. The red solution iscooled to room temperature and the resulting crystalline precipitate isfiltered, washed and dried. It is recrystallized from methylenechloride-ether mixture to give off-white solid (3.4 g), m.p. 135°-5° C.A second run of the reaction with the ester (3.2 g, 0.0123 mole),aniline (1.4 ml, 0.0154 mole) and xylene (100 ml) gives 2.8 g of theanilide. The products from the two runs are combined and recrystallizedfrom methylene chloride-isopropyl ether to give 4.8 g of material, m.p.136°-8° C.

IR (CHCl₃) 3350 (b, OH, NH); 1695 (C═O); 1600 (NH); 1143 (SO₂) cm⁻¹.

NMR (CDCl₃) δ 9.2 (b, 1, OH, NH); 7.5 (m, 7, aromatic); 4.3 (m, ˜3, C₅,C₆). λ_(max) ^(EtOH) 340 (6,600), 252 (21,600) mμ.

Anal. Calcd. for C₁₄ H₁₁ NO₄ S₂ : C, 52.32; H, 3.45; N, 4.36; S, 19.95.Found: C, 52.49; H, 3.62; N, 4.35; S, 19.53, 19.55.

EXAMPLE 5 ##STR9##4-Hydroxy-N-(2-thiazolyl)-6H-thieno[2,3-b]thiopyran-5-carboxamide7,7-dioxide

A mixture of methyl 4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxylate7,7-dioxide (5.2 g, 0.02 mole), 2-aminothiazole (3.0 g, 0.03 mole) andxylene (175 ml) is warmed and filtered from the polymeric products. Thefiltrate is refluxed for 30 min. when some more polymeric product isformed. It is filtered again, and the filtrate refluxed for 1.5 hrs. Themixture is cooled to 5° C. in an ice-bath, and the resulting crystallineproduct is collected. It is dissolved in THF, treated with charcoal andfiltered. The filtrate is concentrated to give the desired product (1.4g, 21%), m.p. 215°-216° C.

IR (Nujol) 3100 (broad, NH and OH); 1590 (CONH); 1155 (SO₂) cm⁻¹.

NMR (DMSO) δ 11.0 (b, ˜2, NH and OH); 8.1 (d, 1, C₃ '); 7.5 (m, 2, C₂-C₃); 7.15 (d, 1, C₄ '); 4.6 (s, 2, CH₂). λ_(max) ^(EtOH) 360 (14,600),267 (12,400), 246 (11,600) mμ; mol. ion. 328.

Anal. Calcd. for C₁₁ H₈ N₂ O₄ S₃ (328): C, 40.23; H, 2.46; N, 8.53; S,29.29. Found: C, 40.38; H, 2.65; N, 8.35 ; S, 28.32, 28.31.

We claim:
 1. A compound of the Formula I: ##STR10## wherein R₁ ishydrogen, halogen or lower alkyl; R₂ is hydrogen, lower alkyl or phenyl;and Ar is isoxazolyl or isoxazolyl substituted with lower alkyl,halogen, lower alkoxy or trifluoromethyl; and its pharmaceuticallyacceptable salts.
 2. A compound according to claim 1, which is4-hydroxy-N-(5-methyl-3-isoxazolyl)-6H-thieno[2,3-b]thiopyran-5-carboxamide7,7-dioxide.